Corticotropin-releasing Factor/Serotonergic Interactions

描述（由申请人提供）：压力是易患衰弱性精神疾病的主要决定因素，包括抑郁、焦虑和药物滥用。本研究的指导目标是确定应激反应的神经介质如何与涉及情绪和行为的神经系统相互作用，从而产生精神和/或行为病理。为了实现这一目标，我们通过证明促肾上腺皮质激素释放因子（CRF）（一种协调应激反应的神经肽）调节中缝背(DR)- 5-羟色胺（5-HT）系统（一种与精神疾病有关的神经递质系统）的活性，确定了压力与情感性障碍之间的关键联系。此外，研究表明，应激史改变了DR-5-HT系统的CRF调节的性质，从抑制到兴奋，这与从主动到被动的应对行为的转变有关。因为被动行为和无法做出决定是抑郁症的特征和衰弱特征，了解这种压力诱导的适应机制，产生它的特定条件及其对药物操作的敏感性将促进我们对抑郁症病理生理学的理解和我们设计适当治疗策略的能力。该竞争性更新提案整合了多种技术方法（PCR，功能神经解剖学，神经生理学，微透析和行为学）和分析水平，以实现以下具体目标：1)确定应激诱导的DR-5-HT系统的CRF调节变化的分子和细胞机制，促进从主动行为向被动行为的转变；2)确定某些社会压力源（如新生儿母亲分离或成人社会压力）是否会导致CRF对DR的调节发生转变，以及这是否导致了这些模型中的抑郁样行为；3)确定传统或新型抗抑郁药物是否可以逆转应激诱导的适应，以及这些药物的机制。个人应对压力的方式是决定身心健康的一个主要因素。拟议的研究将推进我们对以下方面的认识：1)不同应对方式的生物学决定因素；2)压力导致抑郁症衰弱过程的机制；3)如何通过药理学手段控制这一过程，从而指导新型抗抑郁药的开发。

DESCRIPTION (provided by applicant): Stress is a major determinant of vulnerability to debilitating psychiatric disorders including, depression, anxiety and substance abuse. The guiding goal of this research is to determine how neuromediators of the stress response interact with neural systems involved in emotion and behavior to produce mental and/or behavioral pathology. Towards this goal, we identified a critical link between stress and affective disorders by demonstrating that corticotropin-releasing factor (CRF), the neuropeptide that orchestrates the stress response, regulates activity of the dorsal raphe (DR)-serotonin (5-HT) system, a neurotransmitter system implicated in psychiatric disorders. Moreover, it was demonstrated that a history of stress changes the nature of CRF regulation of the DR-5-HT system from inhibition to excitation and that this is associated with a shift from active to passive coping behavior. Because passive behavior and inability to make decisions are characteristic and debilitating features of depression, understanding the mechanism of this stress-induced adaptation, the specific conditions that produce it and its sensitivity to pharmacological manipulation will advance our understanding of the pathophysiology of depression and our ability to design appropriate therapeutic strategies. This proposal for a competing renewal integrates diverse technical approaches (PCR, functional neuroanatomy, neurophysiology, microdialysis and behavior) and levels of analyses to achieve the following Specific Aims: 1) Identify molecular and cellular mechanisms underlying stress-induced changes in CRF regulation of the DR-5-HT system that promote a shift from active to passive behavior; 2) Determine whether certain social stressors (e.g., neonatal maternal separation or adult social stress) produce a shift in CRF regulation of the DR and whether this is responsible for depressive-like behavior in these models; and 3) Determine whether the stress-induced adaptations can be reversed by classical or novel antidepressant agents and the mechanisms by which these agents do this. The manner in which individuals respond to stress is a major factor in determining physical and mental health. The proposed studies will advance our knowledge of 1) the biological determinants of different coping styles, 2) mechanisms by which stress results in the debilitating course of depression and 3) how this can be manipulated by pharmacological agents and thereby guide development of novel antidepressants.